tbuckley/cabot-search huggingface dataset:
Abstract 3720: TACH101, a first-in-class inhibitor of KDM4 histone lysine demethylase for the treatment of diffuse large B-cell lymphoma
Authors: Frank Perabo, Chandtip Chandhasin, Sanghee Yoo, Joselyn Del Rosario, Young K. Chen, Ellen Filvaroff, Jeffrey A. Stafford, Stephen Quake, Michael F. Clarke
Journal: Cancer Research (2022)

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL) in the US accounting for about 22% of newly diagnosed cases of B-cell NHL. It is considered to be more aggressive and to have worse prognosis due to low response to existing treatments. KDM4 is a family of histone demethylases that can drive tumor growth by regulating transcription, cell cycle, and DNA replication/repair. Overexpression of KDM4 alters post-translational histone modification and is associated with many types of cancer, including DLBCL. TACH101 is a novel, potent small molecule inhibitor of KDM4 that is being developed for treatment of advanced cancers, including DLBCL. Methods: TACH101 was evaluated in vitro and in vivo using cancer cell lines and patient-derived organoid (PDO) and xenograft (PDX) models of DLBCL. Results: TACH101 is a reversible, α-ketoglutarate competitive, selective and potent inhibitor of KDM4 isoforms A-D with IC50 values &amp;lt; 0.100 μM for all four isoforms. An initial screen using a 301-cell line panel showed that DLBCL cell lines are sensitive to TACH101 (IC50 &amp;lt; 10 nM). In an additional panel of DLBCL cell lines, TACH101 inhibited proliferation in a dose-dependent manner in all DLBCL cell lines, independent of molecular subtype, with mean IC50’s of 0.03 ± 0.01 μM in ABC DLBCL cell lines (n=6); 0.02 ± 0.01 μM in GCB DLBCL cell lines (n=7) and 0.02 ± 0.01 μM in PMBL DLBCL cell lines (n=2). In OCI-LY19 DLBCL xenografts in vivo, TACH101 was well tolerated and inhibited tumor growth by 55% to 100%, depending on dosing regimen (either QD or BID following a 3 days on/4 days off schedule). In PK studies, TACH101 exhibited low clearance, moderate volume of distribution, and good oral bioavailability in mouse, rat, and dog. Moreover, treatment with TACH101 resulted in little or no inhibitory effects on CYP enzymes. Toxicity studies in rats and dogs identified potential target tissues and provided safety guidance for the use of TACH101 in human studies. Conclusions: The KDM4 inhibitor, TACH101, had compelling activity in preclinical DLBCL models, suggesting that TACH101 could be an effective therapy for DLBCL. Preparations to advance the drug into clinical trials are underway. Citation Format: Frank Perabo, Chandtip Chandhasin, Sanghee Yoo, Joselyn Del Rosario, Young K. Chen, Ellen Filvaroff, Jeffrey A. Stafford, Stephen Quake, Michael F. Clarke. TACH101, a first-in-class inhibitor of KDM4 histone lysine demethylase for the treatment of diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3720.
Closing the loop for patients with Parkinson disease: where are we?
Authors: Hazhir Teymourian, Farshad Tehrani, Katherine Longardner, Kuldeep Mahato, Tatiana Podhajny, Jong-Min Moon, Yugender Goud Kotagiri, Juliane R. Sempionatto, Irene Litvan, Joseph Wang
Journal: Nature Reviews Neurology (2022)
Abstract 715: Targeting the mTOR pathway for the prevention of er-negative breast cancer
Authors: Abhijit Mazumdar, Jamal Hill, William Tahaney, Yanxia Ma, Alejandro Contreras, Shizuko Sei, Altaf Mohammed, Powel Brown
Journal: Cancer Research (2022)

Abstract Background: Triple-Negative breast cancer (TNBC) is an aggressive cancer that lacks expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. These cancers have a poor prognosis and are treated predominantly with chemotherapy. Therefore, we are working to find preventive therapies for these potentially lethal cancers. Dysregulation of PI3K-mTOR pathway is commonly associated with TNBC and other ER-negative breast cancers. We hypothesized that targeting mTOR may prevent development of ER-negative breast cancers and in this study tested whether the mTOR inhibitor, everolimus, prevents cancer in several mouse models of ER-negative breast cancer. Methods: MMTV-erbB2 mice were purchased from the Jackson Laboratory. C3(1)/SV40TAg and BRCA1co/co;MMTV-Cre;p53+/- were generated through breeding. P53-null and p53-mutant mammary gland mice were generated by transplanting p53-null or p53-mutant mammary glands into cleared fat pads of p53-wild type mice. The mice were treated with either control or everolimus (5mg/kg), administered by oral gavage daily (5X/week). All mice develop palpable mammary tumors within 8-12 months. Mice were observed daily for tumor formation and drug toxicity. The percentage of tumor free mice was recorded, and time to tumor development was visualized using Kaplan-Meier curves and analyzed using the generalized Wilcoxon test. Results: Treatment with everolimus significantly increased median survival of all mouse models. Everolimus treatment was also able to completely prevent mammary tumor formation in 27% of C3(1)/SV40Tag mice and 44% p53-mutant mammary gland mice. In p53-null mammary gland mice, 46% of control mice had developed tumors after 420 days, compared to 7% of everolimus treated mice. Long term treatment of everolimus was associated with mild toxicity that includes slight weight loss (&amp;lt;10%) and skin changes (matted hair, skin erythema). Conclusions: Everolimus significantly delayed mammary tumorigenesis in all five breast cancer mouse models. Our results suggest that everolimus is a promising cancer preventive drug for ER-negative tumors, and that further studies of everolimus in combination with other targeted therapies are warranted. In the future, clinical trials of the everolimus should be considered for the prevention of breast cancer in high-risk patients. Supported by NCI PREVENT Cancer Preclinical Drug Development Program (HHSN-2612015000-18I (PB). Citation Format: Abhijit Mazumdar, Jamal Hill, William Tahaney, Yanxia Ma, Alejandro Contreras, Shizuko Sei, Altaf Mohammed, Powel Brown. Targeting the mTOR pathway for the prevention of er-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 715.
Safety and immunogenicity of heterologous boost immunisation with an orally administered aerosolised Ad5-nCoV after two-dose priming with an inactivated SARS-CoV-2 vaccine in Chinese adults: a randomised, open-label, single-centre trial
Authors: Jing-Xin Li, Shi-Po Wu, Xi-Ling Guo, Rong Tang, Bao-Ying Huang, Xiao-Qin Chen, Yin Chen, Li-Hua Hou, Jing-Xian Liu, Jin Zhong, Hong-Xing Pan, Feng-Juan Shi, Xiao-Yu Xu, Zhuo-Pei Li, Xiao-Yin Zhang, Lun-Biao Cui, Wen-Jie Tan, Wei Chen, Feng-Cai Zhu, Jing-Xin Li, Shi-Po Wu, Xi-Ling Guo, Rong Tang, Bao-Ying Huang, Xiao-Qin Chen, Yin Chen, Li-Hua Hou, Jing-Xian Liu, Jin Zhong, Hong-Xing Pan, Feng-Juan Shi, Xiao-Yu Xu, Zhuo-Pei Li, Xiao-Yin Zhang, Lun-Biao Cui, Wen-Jie Tan, Wei Chen, Feng-Cai Zhu, Hai-Tao Huang, Jin-Bo Gou, Wei-Xue Si, Xue Wang, Xiao-Long Zhao, Tao Zhu
Journal: The Lancet Respiratory Medicine (2022)
Abstract 1762: A novel antibody drug conjugate linker enabling production of ADCs with high drug to antibody ratios and fast payload release for improved efficacy
Authors: Noemie Luong, Nathalie Bellocq, Leo Marx, Mathilde Pantin, Benjamin Tchumi, Marie-Claude Roubaudi-Fraschini, Camille Riff, Manfred Mutter, Antoine Attinger
Journal: Cancer Research (2022)

Abstract Antibody drug conjugates (ADCs) represent an attractive approach to bring very cytotoxic drugs into tumors while avoiding systemic toxicities. Currently, most commercially available ADCs come with toxicities associated with the nonspecific release of the payload in the circulation. We have developed a novel drug multi-linker technology that enables the generation of stable and potent ADCs. It is selectively recognized and cleaved by the carboxydipeptidase activity of Cathepsin B that has been shown to be overexpressed in cancer cells. The technology allows for a fast and specific cleavage, which results in efficient drug release in the tumor. Different payloads can be attached to antibodies, and the drug to antibody ratio (DAR) can be modulated up to DAR16, resulting in customed cytotoxic activity. Here we characterize the properties of the multi-linker using different payloads, different DARs, and trastuzumab as the targeting antibody. Trastuzumab based multi-linker ADCs were generated and tested in vitro and in vivo. The linker-payload kinetic release and the cytotoxicity of these ADCs were assessed in vitro. Pharmacokinetic (PK) and pharmacodynamic properties of selected multi-linker ADCs were then investigated in relevant in vivo models and compared to trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-Dxd). Trastuzumab based multi-linker ADCs were shown to efficiently target Her2 expressing cells. In vitro, increasing the DAR had a positive effect on cytotoxicity. In a breast cancer model expressing low levels of Her2, a trastuzumab based multi-linker ADC with mertansine (DM1) at DAR8 showed superior activity, including complete tumor regressions, as compared to T-DM1 and T-Dxd and was well tolerated. In addition, the trastuzumab based multi-linker ADCs showed total antibody PK profiles comparable to T-DM1 and good stability in plasma. In conclusion, these results demonstrate that this novel linker technology can be used to produce stable and high DAR ADCs with improved efficacy. Citation Format: Noemie Luong, Nathalie Bellocq, Leo Marx, Mathilde Pantin, Benjamin Tchumi, Marie-Claude Roubaudi-Fraschini, Camille Riff, Manfred Mutter, Antoine Attinger. A novel antibody drug conjugate linker enabling production of ADCs with high drug to antibody ratios and fast payload release for improved efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1762.
Abstract 5458: Pharmacodynamics of WX-0593 combined with bevacizumab biosimilar on human lung cancer xenograft mouse models
Authors: Shansong Zheng, Qingmei Zheng, Xin Dong, Xinmei Wang, Dongmei Chen, Huicheng Duan, Cuicui Ma, Chenwei Zhang
Journal: Cancer Research (2022)

Abstract Objective: To evaluate the antitumor activity of WX-0593 (anaplastic lymphoma kinase/ROS proto-oncogene 1 receptor tyrosine kinase [ALK/ROS1] tyrosine kinase inhibitor) combined with bevacizumab biosimilar in vivo. Methods: Cell line-derived xenograft (CDX) model: NCI-H3122 cell suspension was subcutaneously inoculated into the right axilla of BALB/c-nu mice. When the average tumor volume reached 100-300 mm3, the mice were randomly divided into six groups (eight mice/group) and administered with solvent, WX-0593 1.5 or 5 mg/kg, bevacizumab biosimilar 1 mg/kg, or WX-0593 1.5 or 5 mg/kg + bevacizumab biosimilar 1 mg/kg, respectively. Patient-derived xenografts (PDX) model: LU-01-1443 tumor tissue blocks of 20-30 mm3 were subcutaneously inoculated into the right axilla of BALB/c-nu mice. When the average tumor volume reached 115 mm3, the mice were randomly divided into four groups (eight mice/group) and administered with solvent, WX-0593 2.5 mg/kg, bevacizumab biosimilar 1.5 mg/kg or their combination. Tumor diameter was measured twice a week. The tolerability was also assessed. Results: CDX tumor model: There were significant differences between each group and the control group (all P &amp;lt;0.01). The combination of WX-0593 5 mg/kg and bevacizumab biosimilar 1 mg/kg was significantly more effective than WX-0593 5 mg/kg alone or bevacizumab biosimilar 1 mg/kg alone (both P &amp;lt;0.01). PDX tumor model: Compared with the control group, single-agent WX-0593 2.5 mg/kg and bevacizumab biosimilar 1.5 mg/kg delayed tumor growth. The tumor suppressive effect of WX-0593 combined with bevacizumab biosimilar was impressive (treated/control ratio =11.81%; tumor growth inhibition =92.19%) and significantly better than WX-0593 2.5 mg/kg or bevacizumab biosimilar 1.5 mg/kg alone (P =0.004, 0.003, respectively). Toxicity: There were no abnormalities in appearance and mental state in each group during the experiment, and the weight of the mice remained stable. Conclusions: The combination of WX-0593 and bevacizumab biosimilar had obvious synergistic effect and showed potent tumor suppressive activity, which was significantly better than WX-0593 or bevacizumab biosimilar alone at the same dose. There was no drug-related toxicity in all groups, and no increase in toxicity after combined administration. Citation Format: Shansong Zheng, Qingmei Zheng, Xin Dong, Xinmei Wang, Dongmei Chen, Huicheng Duan, Cuicui Ma, Chenwei Zhang. Pharmacodynamics of WX-0593 combined with bevacizumab biosimilar on human lung cancer xenograft mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5458.
Human Colon Cancer–Derived <i>Clostridioides difficile</i> Strains Drive Colonic Tumorigenesis in Mice
Authors: Julia L. Drewes, Jie Chen, Nicholas O. Markham, Reece J. Knippel, Jada C. Domingue, Ada J. Tam, June L. Chan, Lana Kim, Madison McMann, Courtney Stevens, Christine M. Dejea, Sarah Tomkovich, John Michel, James R. White, Fuad Mohammad, Victoria L. Campodónico, Cody N. Heiser, Xinqun Wu, Shaoguang Wu, Hua Ding, Patricia Simner, Karen Carroll, Martha J. Shrubsole, Robert A. Anders, Seth T. Walk, Christian Jobin, Fengyi Wan, Robert J. Coffey, Franck Housseau, Ken S. Lau, Cynthia L. Sears
Journal: Cancer Discovery (2022)

Defining the complex role of the microbiome in colorectal cancer and the discovery of novel, protumorigenic microbes are areas of active investigation. In the present study, culturing and reassociation experiments revealed that toxigenic strains of Clostridioides difficile drove the tumorigenic phenotype of a subset of colorectal cancer patient-derived mucosal slurries in germ-free ApcMin/+ mice. Tumorigenesis was dependent on the C. difficile toxin TcdB and was associated with induction of Wnt signaling, reactive oxygen species, and protumorigenic mucosal immune responses marked by the infiltration of activated myeloid cells and IL17-producing lymphoid and innate lymphoid cell subsets. These findings suggest that chronic colonization with toxigenic C. difficile is a potential driver of colorectal cancer in patients. Colorectal cancer is a leading cause of cancer and cancer-related deaths worldwide, with a multifactorial etiology that likely includes procarcinogenic bacteria. Using human colon cancer specimens, culturing, and murine models, we demonstrate that chronic infection with the enteric pathogen C. difficile is a previously unrecognized contributor to colonic tumorigenesis. See related commentary by Jain and Dudeja, p. 1838. This article is highlighted in the In This Issue feature, p. 1825.
Abstract 229: Elucidating arsenic dependent carcinogenesis in humans
Authors: Alma A. Poceros-Coba, Ana Estrada-Florez, Ted Toal, Paul Lott, Macarena Garrido, Craig Steinmaus, Catterina Ferrecio R., Luis Carvajal-Carmona
Journal: Cancer Research (2022)

Abstract Arsenic contamination in drinking water is one of the major health issues worldwide. Over 140 million people from 50+ countries are exposed to drinking water containing arsenic at levels above “safe” levels of 10 μg/L. Several studies indicate that chronic arsenic exposure is associated with the development of carcinogenic changes in the lungs, bladder, liver, and skin and other potential health problems. In this project, we aim to characterize bladder cancer mutational signatures and somatic mutations in a cohort of bladder cancer patients known to have been highly exposed to arsenic in northern Chile by using whole-exome sequencing (WES). We analyzed WES data and identified somatic mutations and mutational signatures using Mutec2 and SigProfiler. Preliminary analyses from a small number of exposed patients identified two mutational signatures, previously described as having “unknown” etiology, that showed an association with arsenic exposure. We are currently validating these findings in additional samples and with functional studies. Alma Poceros-Coba Ph.D. Candidate is the recipient of the Conacyt-UC-MEXUS Doctoral Fellowship and is the recipient of the UCDCCC Travel Award. Citation Format: Alma A. Poceros-Coba, Ana Estrada-Florez, Ted Toal, Paul Lott, Macarena Garrido, Craig Steinmaus, Catterina Ferrecio R., Luis Carvajal-Carmona. Elucidating arsenic dependent carcinogenesis in humans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 229.
Abstract 5816: Serum metabolomic profile of exposure to hair dye
Authors: Jungeun Lim, Jiaqi Huang, Stephanie J. Weinstein, Demetrius Albanes
Journal: Cancer Research (2022)

Abstract Hair dye products now represent one of the most rapidly growing beauty and personal care industries. The association between hair dye use and the development of cancer has been a research focus, including for breast, prostate, and bladder cancer, yet biological mechanisms have not been established. In this first examination of metabolomic response to hair dye exposure, we compared the serum metabolite profiles of male hair dye users and nonusers to identify differences related to biological mechanisms relevant to how exposure may influence cancer risk. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study was a randomized, controlled cancer prevention trial of vitamin supplementation that enrolled 50–69-year-old Finnish male smokers of whom 75 hair dye users and 125 nonusers were studied. Ultrahigh performance liquid chromatography-tandem mass spectrometry was used to assay baseline serum samples, and the difference in log-transformed, batch-normalized metabolite signals between the exposed and unexposed men was estimated using linear regression, adjusting for age, body mass index, and smoking. We measured 1,401 metabolites, of which 11 compounds, including 4 amino acids and 3 xenobiotics, differed significantly between the two groups after correction for multiple comparisons (FDR&amp;lt;0.1). Redox-related glutathione metabolism was heavily represented, including cysteineglutathione disulfide which showed the strongest association with hair dye use (effect size (β) = -0.685; p&amp;lt;0.0001), along with oxidized cysteine-glycine (β = -0.325; p&amp;lt;0.0001) and several compounds relevant to antioxidation/ROS pathways. Metabolites previously associated with prostate cancer risk also differed significantly between hair dye user and non-users. Our findings point to biological mechanisms through which exposure to hair dyes may impact risk of prostate and other cancers. Citation Format: Jungeun Lim, Jiaqi Huang, Stephanie J. Weinstein, Demetrius Albanes. Serum metabolomic profile of exposure to hair dye [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5816.
Abstract 3510: SOT201 is a novel targeted IL-15Rbg agonist to alleviate PD-1-mediated immune cell suppression and potentiate anti-tumor efficacy
Authors: Irena Adkins, Zuzana Antosova, Klara Danova, Kamila Hladikova, Katerina Augustynkova, Katerina Sajnerova, Nada Podzimkova, Pavel Marasek, Guy de Martynoff, David Bechard, Ulrich Moebius, Radek Spisek
Journal: Cancer Research (2022)

Abstract SOT201 is a novel immunocytokine consisting of a monoclonal humanized, Fc silenced antibody against PD-1 fused to a covalent RLI-15 complex of a human IL-15 mutein linked to the high-affinity binding site of the IL-15Rα, the sushi+ domain. SOT201 is developed for immunotherapeutic treatment of various types of cancers. The activity of SOT201 is based on spatiotemporal reinvigorating of anti-tumor immune responses by disrupting co-inhibitory T-cell signaling by blocking PD-1 and synergistically activating adaptive as well as innate immunity by IL-15-mediated signaling via the IL-2/IL-15βγ receptor on T cells, NK, NKT, and γδ T cells. SOT201 showed a superior potentiation of T cell stimulation over pembrolizumab in mixed lymphocyte reaction in vitro. Studies in cynomolgus monkeys showed that decreased affinity of IL-15 mutein in SOT201 for its IL-15Rβγ is well optimized to ensure favorable pharmacokinetic properties while inducing strong CD8+ T cell and NK cell activation and expansion. Synergistic action on CD8+ T cell activation of both anti-PD-1 and RLI-15 moieties was confirmed using mouse surrogate SOT201 molecules in vivo. Strong anti-tumor efficacy after SOT201 treatment was achieved in a human PD-1 transgenic mouse model implanted with the MC38-hPD-L1 cell line. These data represent a promising therapeutic candidate molecule leveraging the synergistic concerted action of anti-PD-1 blockage and simultaneous immune cell activation directed preferentially to the high PD-1+ T cell tumor environment. The therapeutic potential of SOT201 is currently being prepared for evaluation in a Phase I clinical study in metastatic advanced cancer patients as well as for PD-1 resistant/refractory patients as our clinical stage IL-2/IL-15Rβγ agonist SOT101 already showed a clinical benefit in these patients in its ongoing Phase I study. Citation Format: Irena Adkins, Zuzana Antosova, Klara Danova, Kamila Hladikova, Katerina Augustynkova, Katerina Sajnerova, Nada Podzimkova, Pavel Marasek, Guy de Martynoff, David Bechard, Ulrich Moebius, Radek Spisek. SOT201 is a novel targeted IL-15Rbg agonist to alleviate PD-1-mediated immune cell suppression and potentiate anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3510.